Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseases

Abstract

(Figure presented.) Genetic and pharmacologic targeting of the PTEN/PI3K/Akt/mTOR signaling pathway was used as a potential therapeutic strategy in the peripheral neuropathies Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and Charcot Marie Tooth disease type 1A (CMT1A). Abundance of PTEN as the major inhibitor of the PI3K/Akt/mTOR signaling pathway is decreased in HNPP and increased in CMT1A rodent models. Inhibiting mTOR downstream of PTEN improves the behavioral, electrophysiological and histological disease phenotype in a mouse model of HNPP. Genetic targeting of PTEN in Schwann cells only transiently increased myelin growth in CMT1A model mice due to a differentiation defect, which is not present in HNPP nerves.